PRESURGERY STRESS--BIOLOGICAL IMPACT IN BREAST CANCER

以前的动物模型研究已经令人信服地证明：1）实验暴露于各种压力源（例如，电击）对免疫系统具有多种影响，包括自然杀伤（NK）细胞活性的降低; 2）在静脉内注射活肿瘤细胞之前暴露于应激源导致肿瘤清除率降低、转移增加和死亡率增加;和3）应激源暴露对转移风险的这些影响由应激诱导的NK细胞活性抑制介导。目前尚不清楚这种广泛的临床前研究文献与人类癌症的相关性。在这项探索性/发展资助申请中提出的为期两年的研究的目标是调查术前压力对两个变量的影响，这两个变量被确定为癌症患者发生转移性疾病的后续风险的潜在预测因素：术前NK细胞活性水平（和相关免疫变量）和手术相关的肿瘤细胞在血流中的传播。具体目标1：采用纵向受试者间研究设计，调查计划接受原发性乳腺癌手术治疗的妇女术前应激水平的模式和预测因素。乳腺癌患者（n=100）将在门诊手术前接受4次评估：第-7天、第-2天、第-1天（在家中）和第-0天（手术用药前在诊所）。压力的心理生物学评估将包括：自我报告、心血管和内分泌测量。将反应与两个匹配的比较组的反应进行对比：1）计划手术的良性乳腺疾病患者（n=50）;和2）来自社区的未接受手术的健康女性（n=50）。具体目标二：采用纵向受试者间研究设计，检查计划接受乳腺癌手术治疗的女性的NK细胞活性和相关免疫措施的术前水平的模式和预测因素。在上述每次术前评估时，将采集血液样本用于免疫测定。具体目标3：采用纵向受试者间研究设计，探讨计划接受原发性乳腺癌手术治疗的女性血流中乳腺癌细胞术前和术后水平的模式和预测因素。 第-6天和第-0天的血液采集将包括用于评估循环中乳腺癌细胞数量的样本，使用具有新鉴定的高度特异性标志物（乳房珠蛋白）的极灵敏逆转录酶聚合酶链反应（RT-PCR）。在第0天，将额外采集两份样本-一份在手术期间，一份在手术后-以提供物理应激对肿瘤细胞扩散的相对贡献的初步指示，超过术前心理生物学应激。

Previous research with animal models has compellingly demonstrated that: 1) experimental exposures to various stressors (e.g., electric shock) have multiple effects on the immune system, including reductions in natural killer (NK) cell activity; 2) exposures to stressors prior to intravenous injection with live tumor cells results in reduced tumor clearance, increased metastases, and increased mortality; and 3) these effects of stressor exposure on metastatic risk are mediated by stress-induced suppression of NK cell activity. The relevance of this extensive preclinical research literature to human cancer is currently unknown. The goal of the two year research study proposed in this exploratory/development grant application is to investigate the impact of presurgery stress on two variables identified as potential predictors of cancer patients' subsequent risk of developing metastatic disease: presurgery levels of NK cell activity (and related immune variables) and surgery-related dissemination of tumor cells in the blood stream. Specific Aim l: To investigate the patterns and predictors of presurgical stress levels among women scheduled for surgical treatment of primary breast cancer, using a longitudinal between-subjects research design. Patients (n=100) with breast cancer will be assessed on 4 occasions prior to outpatient surgery: Day-7, Day-2, Day-1 (in their homes) and Day-0 (in the clinic prior to medication for surgery). Psychobiological assessments of stress will include: self-report, cardiovascular, and endocrine measures. Responses will be contrasted to those of two matched Comparison Groups: l) patients (n=50) with benign breast disease scheduled for surgery; and, 2) healthy women from the community not undergoing surgery (n=50). Specific Aim 2: To examine the patterns and predictors of presurgical levels of NK cell activity and related immune measures in women scheduled for surgical treatment of breast cancer using a longitudinal between-subjects research design. At each of the presurgery assessments described above, blood samples will be taken for assay of immune measures. Specific Aim 3: To explore the patterns and predictors of pre- and peri- operative levels of breast cancer cells in the blood stream of women scheduled for surgical treatment of primary breast cancer, using a longitudinal between-subjects research design. Blood collection on Day-6 and Day-0 will include samples for assessment of the numbers of breast cancer cells in circulation, using an extremely sensitive reverse- transcriptase polymerase chain reaction (RT-PCR) with a newly identified, highly specific marker (mammaglobin). On Day-0, two additional samples will be collected - one during and one after-surgery - to provide some preliminary indication of the relative contribution of physical stresses to tumor cell dissemination above and beyond preoperative Psychobiological stress.